This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The respiratory illnesses related to influenza virus can be prevented by vaccination. The current inactivated influenza vaccine is effective in eliciting systemic virus-specific antibodies sufficient to control viral replication. However, in order to improve influenza cross-protection the induction of a broader immune response at the site of viral entry may be required. We found that skin immunization of inactivated influenza virus antigen when administered with cholera toxin and the immunomodulators, retinoic acid and oleic acid, results in complete protection 12 weeks post immunization. The use of adjuvants in transdermal vaccination results in substantial antibody titers. In addition, mice vaccinated with retinoic acid show an enhanced mucosal antibody response, increased number of antibody secreting cells in the mucosal tissue, and protection against a higher influenza lethal dose. The results show that transdermal administration of inactivated virus in combination with adjuvants and/or immunomodulators results in long-term systemic and mucosal responses allowing for an effective protective immunity.